Pyridostigmine bromide, chlorpyrifos, and DEET combined Gulf War exposure insult depresses mitochondrial function in neuroblastoma cells

Abstract

Gulf War Illness (GWI) is defined by the Centers for Disease Control and Prevention (CDC) as a multi-symptom illness having at least one symptom from two of three factors, which include: fatigue, mood-cognition problems, and musculoskeletal disorders. The cluster of long-term symptoms is unique to military personnel from coalition countries including United States, Australia, and the United Kingdom that served in Operation Desert Storm from 1990 to 1991. Reporting of these symptoms is much lower among soldiers deployed in other parts of the world like Bosnia during the same time period. The exact cause of GWI is unknown, but combined exposure to N,N-diethyl-m-toluamide (DEET), organophosphates like chlorpyrifos (CPF), and pyridostigmine bromide (PB), has been hypothesized as a potential mechanism.Mitochondrial dysfunction is known to occur in most neurodegenerative diseases that share symptoms with GWI and has therefore been implicated in GWI. Although exposure to these and other toxicants continues to be investigated as potential causes of GWI, their combined impact on mitochondrial physiology remains unknown. In this study, the effects of combined GWI toxicant exposure on mitochondrial function were determined in a commonly used and readily available immortalized cell line (N2a), whose higher rate of oxygen consumption resembles that of highly metabolic neurons in vivo. We report that combined exposure containing pesticide CPF 71 μM, insect repellants DEET 78 μM, and antitoxins PB 19 μM, causes profound mitochondrial dysfunction after a 4-h incubation resulting in decreased mitochondrial respiratory states in the absence of proapoptotic signaling, proton leak, or significant increase in reactive oxygen species production.

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

“…Delic et al . [ 72 ], using a neuronal cell culture model, found that combined exposure to N,N-diethyl-meta-toluamide (DEET), chlorpyrifos, and PB (a combination intended to mimic veterans’ exposure in the GW) caused a large decrease in mitochondrial spare respiratory capacity in 4 hours, at exposure levels that did not affect cell viability at either 4 or 8 hours. Yates et al .…”

“…They are also consistent with recent work in cell culture models. Delic et al [72], using a neuronal cell culture model, found that combined exposure to N,N-diethyl-metatoluamide (DEET), chlorpyrifos, and PB (a combination intended to mimic veterans' exposure in the GW) caused a large decrease in mitochondrial spare respiratory capacity in 4 hours, at exposure levels that did not affect cell viability at either 4 or 8 hours. Yates et al [73] differentiated induced pluripotent stem cells derived from veterans with or without GWI into forebrain glutamatergic neurons, and exposed them to diisopropylflurophosphate (an organophosphate pesticide used as a sarin mimic) and cortisol (to mimic stress); this cellular model of GWI reduced cellular energetics measured as produced reducing power and mitochondrial membrane potential.…”

Gulf war toxicant-induced effects on the hippocampal dendritic arbor are reversed by treatment with a Withania somnifera extract

“…Many pharmacological studies have been performed to characterize the different responses to treatment with W. somnifera extract. Oxidative stress that can affect mitochondria is a characteristic of Gulf War exposures ( Chen et al, 2017 ; Shetty et al, 2017 ; Delic et al, 2021 ). Rats that received intraperitoneal injection of W. somnifera root extract after rotenone-induced oxidative stress had similar levels of antioxidants and lipid peroxidation to non-stress controls, demonstrating the anti-oxidative properties of W. somnifera ( Epuri et al, 2023 ).…”

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

“…They are also consistent with recent work in cell culture models. Delic et al [78], using a neuronal cell culture model, found that combined exposure to N,N-diethyl-meta-toluamide (DEET), chlorpyrifos, and PB (a combination intended to mimic veterans' exposure in the GW) caused a large decrease in mitochondrial spare respiratory capacity in 4 hours, at exposure levels that did not affect cell viability at either 4 or 8 hours. Yates et al [79] differentiated induced pluripotent stem cells derived from veterans with or without GWI into forebrain glutamatergic neurons, and exposed them to diisopropylflurophosphate (an organophosphate pesticide used as a sarin mimic) and cortisol (to mimic stress); this cellular model of GWI reduced cellular energetics measured as produced reducing power and mitochondrial membrane potential.…”